Abstract Androgen Receptor containing novel transcriptional complex for cancer-specific gene expression in therapy-resistant Prostate Cancer. PI: Samikshan Dutta Several studies indicated the importance of AR-regulated gene expression in CRPC, prompting to the development of second-generation anti-androgen therapies such as enzalutamide and abiraterone acetate. These drugs show limited success for treating CRPC patients because of the emergence of several resistant mechanisms, which are either dependent or independent on AR. One such mechanism maintains AR axis in therapy resistant-CRPC by expressing the splice variants of AR that can function despite enzalutamide treatment. AR specific activating mutations are also observed following abiraterone or enzalutamide treatment. To circumvent these resistant mechanisms, a better approach would be to inhibit AR functions directly by targeting its associated components of gene transcription. Our current study has indicated a CRPC-specific transcriptional complex where AR is acting as a member. We observed that the nuclear localization of AR and its splice variant is dependent on Neuropilin-2 (NRP2) in advanced PCa. NRP2 is a glycosylated, non-kinase cell surface protein, whose expression is associated with PCa-specific death. With the help of immunoelectron and super-resolution microscopy we observed NRP2 is present in the nuclear membrane of CRPC cells. Further, mass spectrometry and CHIP-sequencing analysis revealed that NRP2 helps AR and/or its splice variants to bind to the specific chromosome location for gene transcription. We therefore hypothesized that NRP2 in the nucleus is critical for AR driven oncogenic transcription and thus promotes aggressive CRPC. To address the hypothesis, we will study how NRP2-AR interaction induces CRPC specific gene expression. In support of our hypothesis, we found that NRP2 is upregulated following androgen deprivation in PCa cells as well as during metastatic progression in human PCa tissues. We also observed that the expression of nuclear NRP2 increases with higher Gleason pattern. Thus, depleting nuclear NRP2 can be an effective strategy to inhibit the AR-mediated global transcriptional activation in combination with the standard therapy. Current proposal thus implies the potential for the development of novel therapeutic approach against metastatic and therapy-resistant PCa.